Discovery and validation of OMA1 inhibitors ABSTRACT According to the Alzheimer?s Association 5.7 million Americans are living with the disease, a number to reach almost 14 million by 2050. Alzheimer?s disease is the 6th leading cause of death in the United States and one in three seniors will die with dementia. The costs associated with Alzheimer?s mounted to $232 billion in 2017 and are expected to grow to as much as $1,1 trillion by 2050. Yet we still have no therapies available to reverse, halt or even decelerate neurodegeneration in patients with Alzheimer?s. All available medicines only treat the symptoms of the disease, such as memory loss, confusion, depression, anxiety, and sleep changes. Hence there remains a huge unmet medical need for disease modifying treatments, especially considering the rapidly increasing socio-economic burden associated with Alzheimer?s disease. The two neuropathological hallmarks of Alzheimer?s disease are plaques and neurofibrillary tangles. However, Alzheimer?s is a complex disease with many different contributing factors, notably aging itself being a major risk factor. Not surprisingly, clinical trials with amyloid-? and tau targeting therapies resulted only in marginal cognitive benefits for patients further emphasizing the need for novel, alternative, and complementary approaches to treatment. Beginning of 2018 there were 112 medicines in clinical development and there is a shift towards nonamyloid mechanisms of action for drugs in earlier phases of drug development. Still, early diagnosis and clinical trial design remain challenging for Alzheimer?s disease. We have identified a novel molecular mechanism of action that is complementary to the existing treatment strategies for Alzheimer?s disease. Our central hypothesis is that the interplay of age-related extracellular and intracellular alterations, such as cerebrovascular changes, the formation of plaques and neurofibrillary tangles, and inflammation, evoke a mitochondrial stress response, which entails activation of a critical protease. This protease regulates a rate-limiting step of the apoptotic cell death cascade, which results in outer membrane permeabilization and cytochrome c release. For phase 1 of this grant, we will initiate a drug discovery program for inhibitors of this protease. These agents will be useful tool compounds for in vivo proof of concept studies. Moreover, these compounds will form the basis for a drug development program in phase 2 of this grant.